Halogenated methylcyclopropyl ethers

ABSTRACT

The following halogenated methylcyclopropyl ethers have been found useful as general inhalation anesthetics: 1-methoxy1,2,2,3-tetrafluoro-3-chlorocyclopropane, 1-methoxy-1,2,3trifluoro-2,3-dichlorocyclopropane, 1-methoxy-1,2,2-trifluoro3,3-dichlorocyclopropane and 1-methoxy-1,2,2,3-tetrafluoro-3bromocyclopropane.

United States Patent [191 Billings et al.

[ HALOGENATED METHYLCYCLOPROPYL ETHERS [75] Inventors: Charles AldenBillings, Concord;

Gerald Joseph ONeill, Arlington; Charles William Simons, Bedford,

all of Mass.

[73] Assignee: W. R. Grace & Co., Cambridge,

Mass.

[22] Filed: Dec. 5, 1974 [21] Appl. No.: 529,631

Related US. Application Data [62] Division of Ser. No. 451,677, March15, 1974.

[52] US. Cl. 260/611 R; 424/339 51 Int. (11. ..c07c 43/18 [58] FieldofSearch 260/611R [56] References Cited UNITED STATES PATENTS 3,047,6337/1962 Bruson et a] 260/611 R 1 Dec. 23, 1975 3,338,978 8/1967 Moore260/611 R X 3,376,349 4/1968 Bruson et al.... 260/611 R 3,497,563 2/1970Gash 260/611 R Primary Examiner-Bemard Helfin Attorney, Agent, orFirm-Armand McMillan; C. E. Parker [57] ABSTRACT 1 Claim, No DrawingsHALOGENATED METHYLCYCLOPROPYL ETHERS 4 This is a division of applicationSer. No. 451,677, filed Mar. 15, 1974.

THE PRIOR ART In the continuing search for new general inhalationanesthetics, there has been tested in recent years more than one hundredhalogenated aliphatic ethercompounds. While a number of these have beenfound useful for the purpose intended, an examination of the behavior oftypical compounds in the class, as reported by Larsen [FluorineChemistry Reviews 3, pages 38 and 39 1969)], fails to reveal any firmstructural criteria to guide present and future investigato'rs towardspecies of utility. As to ethers involving cyclic structures, on theother hand, the teachings of the art are even less enlightening. Larsenreports in the above cited compendium (on page 40), not one of the fewfluorinated cyclopentyl and cyclohexyl alkyl ethers tested has shown anypromise in the field of anesthesia. The pattern that emerges, if any, isalmost entirely negative. On the subject of the physiological behaviorof the type of compound with which the present disclosure is concerned,i.e. fluorinated cyclopropyl alkyl ethers, the literature is silent.

SUMMARY OF THE INVENTION It has now been discovered that newlysynthesized l-methoxy- 1 ,2,2,3-tetrafluoro-3-chlorocyclopropane,l-methoxyl ,2,3-trifluoro-2,3-dichlorocyclopropane,

1 -methoxy-1 ,2 ,2-trifluoro-3 ,3-dichlorocyclopropane and l-methoxy-l,2,2,3-tetrafluoro-3-bromocyclopropane possess high potency as generalanesthetics when administered to inhalation-anesthetic-susceptibleorganisms.

DETAILED DESCRIPTION The compounds which constitute the basis of thisinvention may be prepared by any of several methods depending on theavailability of starting materials and on the yield consideredacceptable under the circumstances. These methods ultimately involve acyclization reaction between a suitable halocarbene (:CYZ) and anappropriate olefinic compound:

The halocarbene may be generated by the decomposition of a number ofprecursors, including phenyl(- trihalomethyl) mercury compounds,according to the method of D. Seyferth et al [.I. Am. Chem. Soc. 87,4259- (1965)] or a properly halogenated fluoropro- "pylene oxide (J.Org. Chem. 3l, 2312 (1966)]. The

actual method employed in the present instance, as described in thefollowing examples, is an adaptation of a procedure for the generalsynthesis of gemdihalocyclopropanes [Synthesis 2, 112 (1973)].

EXAMPLES l to 4 The quarternary ammonium hydroxide formed (1), beinginsoluble in the reaction mixture, migrates to the boundary between theaqueous'and the organic phases where it reacts with the trihalomethaneto yield the quaternary ammonium derivative of the trihalomethyl anion(2). After diffusion into the organic phase, the derivative istransformed (3) into the carbene :CYZ and the catalyst halide. Thecarbene then reacts with the olefin to yield a cyclopropane compound.

ln'a typical preparation, for instance that of Example 1, 50% aqueoussodium hydroxide, ml, is placed into a 300 ml stainless steel autoclavewith triethylbenzylammonium bromide, 1.0 g, dichlorofluoromethane, 0.75mole, and trifluorovinyl methyl ether, 0.5 mole. The contents of theautoclave are stirred at ambient temperature until all the halogenatedmethane has been consumed, in this case a period of 24 hours. Thereaction mixture is vacuum distilled to collect the or ganic phase andthe distillate is further refined by redistillation after separation ofentrained water. Clear colorless liquid l-methoxy-l ,2,2,3-tetrafluoro-3-chlorocyclopropane is obtained, as identified byspecific gravity and boiling point (Table II), in yield of 16 percent,based on the methane, and 69 percent, based on the olefin.

The olefinic and halogenated methane starting materials employed and theproduct obtained in this other 50 examples are listed in the followingtable.

TABLE I PREPARATION OF CYCLOPROPYL METHYL ETHERS The compounds of TableI are clear colorless liquids at room temperature. They can be stored incontainers of the type commonly used for conventional anesthetics ofcomparable boiling point, e.g. bromochlorotrifluoroethane (halothane),and they can be administered by means of apparatus or machines designedto vaporize liquid anesthetics and mix them with air, oxygen, or othergaseous combinations in amounts capable of supporting respiration. It isfurther contemplated that the compounds may be used in admixture withpharmaceutically acceptable diluents and stabilizers (e.g. thymol), orin combination with one or more of the known inhalation anesthetics,e.g. nitrous oxide, ether, halothane, chloroform and 2,2-dichloro-l,l-difluoroethyl methyl ether (methoxyflurane).

EXAMPLES 5 to 8 The physiological effects of the cyclopropanes preparedin the preceding examples were demonstrated as follows, using a standardtest for evaluation of inhalation anesthetics similar to that describedin Robbins [J Pharmacology and Experimental Therapeutics 86, 197(1946)].

Mice were exposed to the anesthetic for a period of 10 minutes in arotating drum. Observations were then made of the pinch reflex, thecorneal reflex and the return of the righting reflex. At least fourgraded doses were employed to determine the minimum concentra tionrequired to anesthetize 50 percent of the mice used (AC and the minimumconcentration required to kill 50 percent of the mice (LC The anestheticindex (Al) was then calculated from these minimum concentrations. Theresults of these tests are summarized in the following table.

TABLE II ANESTHETIC PROPERTIES OF l-METHOXY-CYCLOPRglIANES As theseresults indicate, four effective inhalation anesthetic agents have beenadded to the art. Their potency and safety can be better visualized bycomparing the values reported in Table [Ito those obtained for the twowell known anesthetics ethyl ether and halothane, under the same testingconditions, namely an anesthetic concentration (AC of about 3.7 and 0.80respectively and an anesthetic index (LC5o/AC of 3.2 and 3.4, alsorespectively. The compounds of the invention, therefore, are as potentas widely used halothane and yet possess a greater margin of safety inadministration than either ether or halothane, as shown by theirrespective anesthetic indexes.

It should be understood that the concentration of any.-

of the above compounds employed for anesthetic purposes must depend onthe subject to be anesthetized, the level of anesthesia desired, therate at which this state is to be induced and the period of time duringwhich it is to be maintained. Such variations .falls within the spiritand the scope of the present invention as claimed.

What we claim is:

l. The methyl cyclopropyl ethers of the class consisting of l-methoxy-1,2,2,3-tetrafluoro-3-chlorocyclopropane,l-methoxy-l,2,3-trifluoro-2,3-dichlorocyclopro' pane, l-methoxy-l,2,2-trifluoro-3 ,3-dichlorocyclopropane and l-methoxy-l ,2,2,3tetrafluoro-3-bromocyclopropane. I

1. THE METHYL CYCLOPROPYL ETHERS OF THE CLASS CONSISTING OF1-METHOXY-1,2,2,3-TETRAFLUORO-3-CHLOROCYCLOPROPANE,1METHOXY-1,2,3-TRIFLUORO-2,3-DICHLOROCYCLOPROPANE,1METHOXY-1,2,3-TRIFLUORO-3,3-DICHLOROCYCLOPROPANE, AND1METHOXY-1,2,2,3-TETRAFLUORO-3-BROMOCYCLOPROPANE.